Genetic knockdown of YB-1 in Group 3 medulloblastoma cell lines diminished cell invasion in 3D in vitro assays and increased sensitivity to standard-of-care chemotherapeutic vincristine and anti-cancer agents panobinostat and JQ1. To address this, we undertook a targeted approach focused on the multi-functional transcription factor YB-1. Accordingly, the identification of targets that mark drug-resistant cell populations, or drive the proliferation of resistant cells, may improve treatment strategies. Therapy resistance represents an unmet challenge in the treatment of medulloblastoma. Together, our findings reveal important mechanisms and genes underlying therapy resistance in medulloblastoma and provide routes to their intervention. Importantly, through the generation of cell lines resistant to standard-of-care medulloblastoma therapies, we identify a drug-tolerant gene expression signature which may represent global, targetable mediators of medulloblastoma drug resistance. We also identify functions for YB-1 in cell invasion, lipid metabolism and activation of the MYC oncoprotein.

Accordingly, we reveal roles for YB-1 in therapy sensitivity and the regulation of the multi-drug resistance gene ABCB1. Here, we investigate mechanisms surrounding medulloblastoma therapy resistance, both related to and independent from oncoprotein YB-1. A barrier to effective medulloblastoma treatment is cellular resistance to standard-of-care therapies.

Under standard therapy, relapse occurs in 30% of patients and is almost universally fatal, accounting for 10% of all childhood cancer deaths. Medulloblastoma is the most common malignant childhood brain tumour.

Between the lines kd williamson